Disclosed herein are 2'-spiro-nucleosides of formula I and derivatives thereof useful for treating a subject infected by hepatitis C virus or dengue virus. Formula (I), where z is a four-or five-membered ring selected from among radicals a-o represented by de following structures (II) where * represents the point of attachment to the 2'-carbon.

1) -P*(0)(ORlc)~, when Y is -0~, where Rlc is defined above, m) -P(0)(OH)-0-P(0)(OH)2,

n) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

o) an C2-7acyl,

p) an aminoacyl,

q) a Ci_6-alkylene-oxy-C2-7acyl, and

r) a -C(0)-0-Ci-6alkyl;

2) R2 is hydrogen;

3) R3 is hydrogen;

4) Y is selected from among

a) -OH,

b) -0~, when R1 is -P(0)(ORlc)~, where Rlc is defined above, c) -0(C2-7acyl), and

d) -O(aminoacyl);

-;

is a four- or five-membered ring selected from among radicals

d, e, and f represented by the following structures

c d e f

* represents the point of attachment to the 2'-carbon and where

a) A is -0-,

b) D is -O- or -CH2-,

c) R4, R5, R8, and R9 are each hydrogen; and

7a) m is 0, is a double-bond and R and R are independently selected from among

i) hydrogen,

ii) -NH2,

iii) -NH(C1-6alkyl),

iv) -NH(C2_7acyl),

iv) -NH-C(0)-0-C!.6alkyl,

v) - cycloheteroalkyl,

vi) -0(C1-6alkyl),

vii) -0(C2- acyl),

viii) -0(Ci-6alkyleneoxyacyl),

ix) -0-C(0)-0-Ci-6alkyl,

x) -S(Ci-6alkyl), and

xi) -OCi_3alkaryl,

7b) m is 1 , is a single-bond and

bl) R16 is selected from among

i) =0,

b2) R17 is selected from among

i) -NH2,

ii) -NH(Ci-6alkyl),

iii) -NH(C2.7acyl),

iv) -NH-C(0)-0-C1-6alkyl, and

v) - cycloheteroalkyl,

7c) independent of the value of m, each bonding pair, W1— W2, W2~ „C, C^W4, W^W3, and W^W1, contained in the five- membered ring comprises a single or a double bond and

i) W1 is O, S, N, or CR14,

ii) W2 is N or CR15,

iii) W3 is C or N, and

iv) W4 is C or N, and

where R— and R15, if present, are independently selected from among i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH2,

iv) C1-6alkyl,

vii) vinyl, and

viii) ethynyl.

17. The compound or its stereoisomer or its salt or its metabolite or its deuterid lee tthheerreeooff aaccccoorrddiinngg ttco claim 12, wherein W1, W2, W3, and W4 are as represented by formula 1-3-1

1-3-1

and wherein

1) R1 is selected from among:

a) hydrogen,

b) -P(0)(OH)2,

c) -P*(0)(ORla)(NHCHRlbC(0)ORIc),

wherein

Rla is

i) hydrogen or

ii) aryl,

Rlb is

i) hydrogen or

ii) Ci-6alkyl, and

Rlc is

i) hydrogen

ii) Ci_6alkyl,

iii) C3.6cycloalkyl, or

iv) Ci-3alkaryl,

d) a l ,3,2-dioxaphosphinane-2-oxide,

e) a 4H-benzo[d][l ,3,2]dioxaphosphinine-2-oxide,

f) -P*(O)(ORl0)~, when Y is -0~, where Rlc is defined above, g) -P(0)(OH)-0-P(0)(OH)2,

h) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

i) a C2-7acyl, and

j) an aminoacyl; and

2) Y is selected from among

a) -OH,

b) -0~, when R1 is -P(O)(ORl0)~, where Rlc is defined above, c) -0(C2-7acyl), and

-O(aminoacyl); and selected from among

where * represents the point of attachment to the 2'-carbon; and

4a) m is 0, is a double-bond

4al) R16 is selected from among

i) -NH2,

ii) -NH(C1-6alkyl),

iii) -NH(C2-7acyl),

iv) -cycloalkylamino,

v) -0(C1-6alkyl),

vi) -0(C2-7acyl),

vii) -0(Ci-6alkyleneoxyacyl), and viii) -0-C(0)-0-Ci-6alkyl,

ix) -S(C1-6alkyl), and

x) -OCi-3alkaryl, and

4a2) R17 is selected from among

i) hydrogen,

ii) -NH2, and

iii) -NH(Ci-6alkyl), or

4b) m is 1 , is a single-bond

4bl) R16 is =0; and

4b2) R17 is selected from among

i) -NH2 and

ii) -NH(C1-6alkyl).

18. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 17, wherein

1) R1 is selected from among:

a) hydrogen,

b) -P(0)(OH)2,

c) -P*(0)(ORla)(NHCHRlbC(0)ORlc),

wherein

Rla is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphthyl, i) hydrogen or

ii) Ci-6alkyl, and

Rlc is

i) hydrogen

ii) Ci-6alkyl,

iii) C3-6cycloalkyl,

iv) Ci_3alkaryl,

d) -P*(0)(ORlc)~, when Y is -0~, where Rlc is defined above, e) -P(0)(OH)-0-P(0)(OH)2,

f) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

g) a C2.7acyl, and

h) an aminoacyl; and

2) Y is selected from among

a) -OH,

b) -0~, when R1 is -P(0)(ORlc)~, where Rlc is defined above, c) -0(C2_7acyl), and

d) -O(aminoacyl); and

where * represents the point of attachment to the 2'-carbon; and

4a) m is 0, is a double-bond

4al) R16 is selected from among

i) -NH2,

ii) -NH(C,.6alkyl),

iii) -NH(C2-7acyl),

iv) -cycloalkylamino,

v) -0(C1-6alkyl),

vi) -0(C2.7acyl),

vii) -0(Ci_6alkyleneoxyacyl), and viii) -0-C(0)-0-Ci-6alkyl,

ix) -S(C1-6alkyl), and

x) -OCi-3alkaryl, and

4a2) R17 is selected from among

i) hydrogen,

ii) -NH2 and

iiii) -NH(C1-6alkyl), or

4b) m is 1 , is a single-bond

4bl) R16 is =O and

4b2) R17 is selected from among

i) -NH2 and

ii) -NH(Ci-6alkyl). 19. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 17, wherein

1) R1 is selected from among:

a) hydrogen,

b) -P(0)(OH)2,

c) -P*(0)(ORIa)(NHCHRIbC(0)ORlc),

wherein

Rla is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl, v) p-bromophenyl, or

vi) naphthyl,

Rlb is

i) hydrogen or

ii) Ci-6alkyl, and

Rlc is

i) hydrogen

ii) Ci-6alkyl,

iii) C3_6cycloalkyl, or

iv) C]-3alkaryl,

d) -P*(0)(ORlc)~, when Y is -0~, where Rlc is defined above, e) -P(0)(OH)-0-P(0)(OH)2,

f) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

g) a C2-7acyl, and

h) an aminoacyl; and

is selected from among

a) -OH,

b) -0~, when R1 is -P(0)(ORlc)~, where Rlc is defined above, c) -0(C2-7acyl), and

-O(aminoacyl); and

3)

w Ρhere *· represe 'nόts the· point attachment to 2'-carbon; and

4a) m is 0, is a double-bond

4al) R16 is selected from among

i) -NH2,

ii) -NH(C1-6alkyl),

iii) -NH(C2-7acyl),

iv) -cycloalkylamino,

v) -0(C1-6alkyl),

vi) -0(C2-7acyl),

vii) -S(Ci.6alkyl), and

viii) -OCi-3alkaryl, and

4a2) R17 is selected from among

i) hydrogen,

ii) -NH2, and

iii) -NH(C1-6alkyl), or

4b) m is 1 , is a single-bond

4bl) R16 is =O and

1 7

4b2) R is selected from among

i) -NH2 and

ii) -NH(C1-6alkyl).

20. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 17, wherein

1) R1 is selected from among: a) hydrogen,

b) -P(0)(OH)2,

c) -P*(0)(ORla)(NHCHRlbC(0)OR10),

wherein

Rla is

i) hydrogen,

ii) phenyl,

iii) p- fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphtyl,

Rlb is

i) hydrogen or

ii) C1-6alkyl, and

Rlc is

i) hydrogen

ii) C].6alkyl,

iii) C3_6cycloalkyl, or

vi) Ci-3alkaryl,

d) -P*(0)(ORlc)~, when Y is -0~, where Rlc is defined above, e) -P(0)(OH)-0-P(0)(OH)2,

f) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

g) a C2-7acyl, and

h) an aminoacyl; and

2) Y is selected from among

a) -OH,

b) -0~, when R1 is -P(0)(ORlc)~, where Rlc is defined above, c) -0(C2-7acyl), and

d) -O(aminoacyl); and

where * represents the point of attachment to the 2'-carbon; and

4a) m is 0, is a double-bond

4al) R16 is -0(C]-6alkyl), -OC].3alkaryl, -S(Ci-6alkyl), -NH(d

6alkyl), or -cycloalkylamino, and

4a2) R17 is -NH2 or -NH(Ci-6alkyl), or

4a3) R16 is -NH2, -0(C1-6alkyl), -OCi-3alkaryl, -S(Ci-6alkyl),

-NH(Ci-6alkyl), or -cycloalkylamino, and

4a4) R17 is hydrogen, or

4b) m is 1, is a single-bond

4bl) R16 is =O and

4b2) R17 is-NH2 or -NH(C1-6alkyl).

21. The compound or its stereoisomer or its salt or its metabolite or its deuteri ddee tthheerreeooff aaccccoorrddiinngg ttoo claim 12, wherein Y, W1, W2, W3, and W4 are as represented by formula 1-3-2

22. The compound or its stereoisomer or its salt or its metabolite or its deuteri ddee tthheerreeooff aaccccoorrddiinngg ttco claim 12, wherein R1, Y, W1, W2, W3, and W4 are as re resented by formula 1-3-3

23. The compound or its stereoisomer or its salt or its metabolite or its deuteri ddee tthheerreeooff aaccccoorrddiinngg ttco claim 12, wherein Y, Z, W1, W2, W3, and W4 are as represented by formula 1-3-4

28. The compound or its stereoisomer or its salt or its metabolite or its deuteri ddee tthheerreeooff aaccccoorrddiinngg ttco claim 12, wherein R1, Y, W1, W2, W3, and W4 are as represented by formula 1-3-7

29. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 1, wherein B is selected from among B5, B6, B7, B8, B9, and BIO represented by the following structures

38. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 29, wherein B' is B10 as represented by formula 1-3-13

1-3-13

wherein

1) R is selected from among:

a) hydrogen,

b) -P(0)(OH)2,

c) -P*(0)(ORla)(NHCHRlbC(0)ORlc),

wherein

RIa is

i) hydrogen or

ii) aryl,

Rlb is

i) hydrogen or

ii) Ci-6alkyl, and

Rlc is i) hydrogen

ii) alkyl,

iii) cycloalkyl, or

iv) -C1-3alkaryl,

d) a l ,3,2-dioxaphosphinane-2-oxide,

e) a 4H-benzo[d][l ,3,2]dioxaphosphinine-2-oxide,

f) -P*(0)(ORlc)~, when Y is -0~, where Rlc is defined above, g) -P(0)(OH)-0-P(0)(OH)2,

h) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

i) a C2-7acyl,

j) an aminoacyl,

k) a Ci-6-alkylene-oxy-acyl, and

l) a -C(0)-0-C1-6alkyl,

2) R2 is hydrogen;

3) R3 is hydrogen or cyano;

4) Y is selected from among

a) -OH,

b) -0~, when R1 is -P(0)(ORlc)~, where Rlc is defined above, c) -0(C2-7acyl),

d) -O(aminoacyl), and

e) -0(Ci_6-alkylene-oxyC2-7acyl);

where * represents the point of attachment to the 2'-carbon; and

7a) m is 0, is a double-bond,

7al ) R16 is selected from among

i) -NH2,

ii) -NH(C1-6alkyl),

iii) -NH(C2-7acyl),

iv) -0(C1-6alkyl),

v) -0(C2-7acyl),

vi) -0(Ci_6alkyleneoxyacyl),

vii) -0-C(0)-0-C]-6alkyl,

viii) -S(C1-6alkyl), and

ix) -OC]-3alkaryl,

7a2) R17 is selected from among

i) hydrogen,

ii) -NH2 and

iii) -NH(C1-6alkyl), or

7b) m is 1 , is a single-bond,

7bl) R16 is =0;

7b2) R17 is selected from among

i) -NH2 and

ii) -NH(C1-6alkyl) and

7c) independent of the value of m, R15 is selected from among

i) hydrogen, ii) halo,

iii) cyano,

iv) -C(0)NH2,

iv) Ci-6alkyl,

vii) vinyl, and

viii) ethynyl.

39. A composition comprising the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 and a pharmaceutically acceptable medium.

40. A composition for treating a hepatitis C virus, which comprises an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 and a pharmaceutically acceptable medium.

41. A composition for treating a dengue virus, which comprises an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 and a pharmaceutically acceptable medium.

42. A method of treating a subject infected by a virus, which comprises: administering to the subject an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38;

wherein the virus is selected from among hepatitis C virus, West Nile virus, a yellow fever virus, a dengue virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, and a Japanese encephalitis virus. 43. A method of treating a hepatitis C virus infection in a subject in need thereof, which comprises:

administering to the subject an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38.

44. A method of treating a dengue virus infection in a subject in need thereof, which comprises:

administering to the subject an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38.

45. A use of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 for the manufacture of a medicament for the treatment of a condition that results from an infection by hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus.

46. A use of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 for the manufacture of a medicament for the treatment of a condition that results from an infection by hepatitis C virus.

47. A use of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 for the manufacture of a medicament for the treatment of a condition that results from an infection by dengue virus.

48. A process for preparing the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof of as claimed in any one of claims 1-38 as disclosed by any of the procedures disclosed herein.

49. A product comprising the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in any one of claims 1-38 obtained by a process as disclosed by any of the procedures disclosed herein.

50. A method of treating a hepatitis C virus (HCV) or dengue (DENV) infection, which comprises adding to the 3 '-terminus of an HCV or DENV RNA strand a radical or its salt thereof represented by

where is the point of attachment to the 3'-terminus.

51. The method of claim 50, which comprises adding the radical or its salt thereof to the 3 '-terminus of an HCV RNA.

52. The method of claim 50, which comprises adding the radical or its salt thereof to the 3 '-terminus of a DENV RNA.

53. A method of treating a hepatitis C virus (HCV) or dengue (DENV) infection, which comprises increasing an intracellular concentration of a triphosphate (P3) compound or its salt thereof or re resented by

in a cell infected with HCV or DENV.

54. The method of claim 53, which comprises increasing the intracellular concentration of the triphosphate (P3) compound in an HCV infected cell.

55. The method of claim 53, which comprises increasing the intracellular concentration of the triphosphate (P3) compound in a DENV infected cell.

56. A compound or a salt thereof represented by formula A,

wherein each one of Z1, Z2, and Z3 is hydrogen or a protecting group (PG).

A process for preparing a compound represented by formula 1-3-4'

1-3-4'

wherein

is selected from among:

a) hydrogen,

b) -P(0)(OH)2,

c) -P*(0)(ORla)(NHCHRlbC(0)ORlc),

wherein

Rla is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphthyl,

Rlb is

i) hydrogen or

ii) C).6alkyl, and

Rlc is

i) hydrogen

ii) C1-6alkyl,

iii) C3-6cycloalkyl, or

iv) Ci-3alkaryl,

d) -P(0)(OH)-0-P(0)(OH)2,

e) -P(0)(OH)-0-P(0)(OH)-0-P(0)(OH)2,

f) a C2-7acyl, and

g) an aminoacyl; and

or

a compound represented by formula 1-3-5',

1-3-5'

wherein

1) Rla is

a) hydrogen,

b) phenyl, or

c) naphthyl, and

2) Rlc is

a) hydrogen

b) C1-6alkyl,

c) C3-6cycloalkyl, or

d) Ci-3alkaryl; and

3) R16 is

a) -0(C,_6alkyl),

b) -OCi-3alkaryl,

c) -S(Ci-6alkyl),

d) -NH(C1-6alkyl), or

e) -cycloalkylamino,

said process comprising

reacting compound A' with a nucleophile and optionally deprotecting to obtain compound B'

wherein the nucleophile is comprised of a radical selected from among -0(C1-6alkyl), -OC1-3alkaryl, -S(C1-6alkyl), -NH(Ci-6alkyl), and -cycloalkylamino, and wherein PG is a protecting group, and wherein each one of Z1, Z2, and Z3 is hydrogen or a protecting group (PG) and

reacting B' with an appropriate reagent to obtain either 1-3-4' or 1-3-5'.

58. The process according to claim 57 for preparing the compound represented by formula 1-3-5', wherein R16 is a -0(Ci.6alkyl). a -OCi-3alkaryl, a - NH(C!-6alkyl), and a C3-6cycloalkylamino and wherein the nucleophile is comprised of a radical selected from among a -0(C] -6alkyl), a -OCi_3alkaryl, a -NH(Ci_6alkyl), and a

C3-6cycloalkylamino.

59. The process according to claim 57 for preparing the compound represented by formula 1-3-5', wherein R16 is a -0(Ci-6alkyl) or a -OCi-3alkaryl, and wherein the nucleophile is comprised of a radical selected from among a -0(C\. 6alkyl) and a

-OCi_3alkaryl.

60. The process according to claim 57 for preparing the compound represented by formula 1-3-5', wherein R16 is a -0(Ci-6alkyl), and wherein the nucleophile is comprised of a-0(Ci_6alkyl).

61. The process according to claim 58 for preparing the compound represented by formula 1-3^5', wherein R16 is a -OCi_3alkaryl, and wherein the nucleophile is comprised of a-OCi-3alkaryl.

wherein Rla is phenyl or naphthyl; Rlc is hydrogen, Ci-6alkyl, C3-6cycloalkyl, or Ci-3alkaryl; R16 is -0(C1-6alkyl), -OCi_3alkaryl, -S(C1-6alkyl), -NH(Ci_6alkyl), or

17

-cycloalkylamino; and R is -H or -NH2

said process comprising reacting a compound represented by formula B'" with a phosphoramidate represented by formula C to obtain 1-3-5'"

B'" C

wherein the phosphoramidate is comprised of a mixture of the S?- and i?P- diastereomers.

Description:

COMPOUNDS

This application is being filed on 29 November 2011, as a PCT International Patent application in the name of Pharmasset, Inc., a U.S. national corporation, applicant for the designation of all countries except the US, and Jinfa Du and

Michael Joseph Sofia, both citizens of the U.S., applicants for the designation of the US only.

Priority

Priority is claimed to U.S. provisional patent application 61/417,946, filed on

November 30, 2010.

Field of the Invention Disclosed herein are 2'-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections.

Background Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. According to the U.S. Center for Disease Control, there are an estimated 4.5 million infected people in the United States alone. According to the World Health

Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver- destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection.

The HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids. The protein products of the HCV gene consist of the structural proteins C, El, and E2, and the non- structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are believed to provide the catalytic machinery for viral replication. The NS3 protease releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain. HCV NS5B polymerase is required for the synthesis of a double-stranded RNA from a single-stranded viral RNA that serves as a template in the replication cycle of HCV. Therefore, NS5B polymerase is considered to be an essential component in the HCV replication complex (K. Ishi, et al, Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249: 108-118). Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.

HCV belongs to a much larger family of viruses that share many common features. Dengue viral infections are problematic in the tropical and subtropical regions of the word. Shi et al. Top. Med. Chem. (2001) 7: 243-276. The dengue virus (DENV) is transmitted to humans by certain mosquitos, and it is has been estimated that up to about 50 million infections occur each year. Parkinson et al. Future Med. Chem. (2010) 2(7): 1181-1203. At the present, there are no specific treatments for dengue viral infections. Fagundes et al. Drug Development Research (2011) 72: 480-500. DENV is comprised of ten proteins that includes three structural proteins (C, prM, and E) and seven non-structural proteins (NS 1 , NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Of these ten proteins, only NS3 and NS5 are known to possess enzymatic activity. A desirable drug substance is one that interferes with the action or function of any one of these ten viral proteins. Flaviviridae Viruses

characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans. Pestiviruses and hepaciviruses are closely related virus groups within the

Flaviviridae family. Other closely related viruses in this family include the GB virus A, GB virus A-like agents, GB virus-B and GB virus-C (also called hepatitis G virus, HGV). The hepaci virus group (hepatitis C virus; HCV) consists of a number of closely related but genotypically distinguishable viruses that infect humans. There are at least 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV virus.

The genetic organization of pestiviruses and hepaciviruses is very similar. These positive stranded RNA viruses possess a single large open reading frame (ORF) encoding all the viral proteins necessary for virus replication. These proteins are expressed as a polyprotein that is co- and post-translationally processed by both cellular and virus-encoded proteinases to yield the mature viral proteins. The viral proteins responsible for the replication of the viral genome RNA are located within approximately the carboxy-terminal. Two-thirds of the ORF are termed

nonstructural (NS) proteins. The genetic organization and polyprotein processing of the nonstructural protein portion of the ORF for pestiviruses and hepaciviruses is very similar. For both the pestiviruses and hepaciviruses, the mature nonstructural (NS) proteins, in sequential order from the amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5 A, and NS5B.

The actual roles and functions of the NS proteins of pestiviruses and hepaciviruses in the lifecycle of the viruses are directly analogous. In both cases, the NS3 serine proteinase is responsible for all proteolytic processing of polyprotein precursors downstream of its position in the ORF (Wiskerchen and Collett,

A number of potential molecular targets for drug development of direct acting antivirals as anti-HCV therapeutics have now been identified including, but not limited to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase and the NS5B polymerase. The RNA-dependent RNA polymerase is absolutely essential for replication of the single-stranded, positive sense, RNA genome and this enzyme has elicited significant interest among medicinal chemists.

Nucleoside inhibitors of NS5B polymerase can act either as a non-natural substrate that results in chain termination or as a competitive inhibitor which competes with nucleotide binding to the polymerase. To function as a chain terminator the nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site. This conversion to the triphosphate is commonly mediated by cellular kinases which imparts additional structural requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation. In some cases, the biological activity of a nucleoside is hampered by its poor substrate characteristics for one or more of the kinases needed to convert it to the active triphosphate form. Formation of the monophosphate by a nucleoside kinase is generally viewed as the rate limiting step of the three phosphorylation events. To circumvent the need for the initial phosphorylation step in the metabolism of a nucleoside to the active triphosphate analog, the preparation of stable phosphate prodrugs has been reported. Nucleoside phosphoramidate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (McGuigan, C, et al., J. Med. Chem., 1996, 39, 1748-1753; Valette, G., et al., J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al., Proc. National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20, 1091-1098; Lee, W.A., et al., Antimicrobial Agents and Chemotherapy, 2005, 49, 1898); US 2006/0241064; and WO 2007/095269. Also limiting the utility of nucleosides as viable therapeutic agents is their sometimes poor physico chemical and pharmacokinetic properties. These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of nucleosides have been employed. Additional phosphate-containing prodrugs are also known: C. Schultz, Biorg. & Med. Chem. (2003) 1 1 :885-898; C. McGuigan et al., Bioorg. & Med. Chem. Lett. (1994) 4(3): 427-430; C. Meier, Synlett (1998) 233-242; R. J. Jones et al., Antiviral Research (1995) 27: 1-17; G. J. Friis et al., Eur. J. Pharm. Sci. (1996) 4: 49-59; C. Meier Mini Reviews in Medicinal Chemistry (2002) 2(3): 219- 234; C. Perigaud et al., Advances in Antiviral Drug Design; DeClerq E., Ed.; Vol. 2; JAI Press, London, 1996. However, there is no general agreement as to which phosphate-containing prodrug provides for the best activity. In an effort to improve treatment of HCV or DENV, it remains of vital interest to identify compounds capable of inhibiting the action of NS5B polymerase of HCV or of inhibiting the action or function of a particular DENV protein.

Summary

Disclosed herein is a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula I:

and where R 14 and R 15 , if present, are independently selected from among

i) hydrogen,

ii) halo,

iii) cyano,

iv) -C(0)NH 2 ,

iv) C 1-6 alkyl,

vii) vinyl, and

viii) ethynyl.

Detailed Description of the Invention

Definitions

The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

The terms "optional" or "optionally" as used herein means that a

subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.

The term "stereoisomer" has its plain and ordinary meaning.

The term "*" denotes the presence of a chiral center. Instances where "*" are not explicitly included in a radical does not necessarily mean that the radical does not contain a chiral center.

The term "P*" means that the phosphorus atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of "R" or "S" which have their accepted plain meanings. In some instances, a phosphorus-containing radical does not expressly include an "*" next to the phosphorus atom, e.g., -P(0)(0(CH 2 )i. 3 OC(0)(alkyl)) 2 ,

-P(0)(0(CH 2 )i -3 SCH 2 (aryl)) 2 . In these (and other) instances, it will be understood that chirality at phosphorus will be dictated by the substituent pattern. That is, when the substituents bound to phosphorus are the same, then achirality at phosphorus will exist, but when the substituents bound to the phosphorus are not the same, then chirality at phosphorus will exist.

The term "salts" or "salt thereof as described herein, refers to a compound comprising a cation and an anion, which can prepared by any process known to one of ordinary skill, e.g., by the protonation of a proton-accepting moiety and/or deprotonation of a proton-donating moiety. Alternatively, the salt can be prepared by a cation/anion metathesis reaction. It should be noted that protonation of the proton-accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a anion, whereas deprotonation of the proton- donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a cation. It is understood that salt formation can occur under synthetic conditions, such as formation of pharmaceutically acceptable salts, or under conditions formed in the body, in which case the corresponding cation or anion is one that is present in the body. Examples of common cations found in the body include, but are not limited to: H + , Na + , K + , g 2+ , Ca 2+ , etc. Examples of common anions found in the body include, but are not limited to, C1-, HCO3 " , C0 3 2" , H 2 P0 4 " , HP0 4 2" , etc.

The phrase "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. It is understood that the term "pharmaceutically acceptable salt" is encompassed by the expression "salt." Examples of

pthylenediamine, meglumine, and procaine. The term "metabolite," as described herein, refers to a compound produced in vivo after administration of a compound or its stereoisomer or its salt or its deuteride thereof represented by formula I to a subject in need thereof or as formed in vitro in an assay. Said metabolite may exist as a salt.

The term "deuteride," as described herein, refers to a deuterated analog of the compound represented by formula I where a hydrogen atom is enriched with its 2 H- isotope, i.e., deuterium (D). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium. .

The term "halo" or "halogen" as used herein, includes chloro, bromo, iodo and fluoro.

The term "C 1-6 -alkylene" refers to an alkylene radical containing 1 to 6 carbon atoms. Examples of a C 1-6 -alkylene include, but are not limited to, a methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), methyl-ethylene (-CH(CH 3 )CH 2 -), propylene (-CH 2 CH 2 CH 2 -), methyl-propylene (-CH(CH 3 )CH 2 CH 2 - or - CH 2 CH(CH 3 )CH 2 -), etc. It is understood that a branched C ]-6 -alkylene, such as methyl-ethylene or methyl-propylene, contains a chiral center, in which case the individual stereoisomers are contemplated. It is contemplated that a methylene may be substituted with one or two C 1-6 alkyls.

The term "cycloalkyl" refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., a C 3-8 -cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., a C 3-6 -cycloalkyl). In the instance of a substituted carbocycle containing 3 to 10, 3 to 8, or 3 to 6 carbon atoms, the substituents are not to be counted for the carbocycle carbon count. For instance, a cyclohexyl substituted with one or more Q^-alkyl is still, within the meaning contemplated herein, a C 3 _ 6 -cycloalkyl. Examples of a C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, 2- methyl-cyclobutyl, cyclopentyl, 2-methyl-cylcopentyl, cyclohexyl, 2-methyl- cyclohexyl, etc.

The term "cycloalkylamino" refers to a unsubstituted or substituted carbocycle comprising an "amino" (-NH-) functional group. The carbocycle contains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., a C 3-8 - cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., a C 3-6 -cycloalkyl). In the instance of a substituted carbocycle containing 3 to 10, 3 to 8, or 3 to 6 carbon atoms, the substituents are not to be counted for the carbocycle carbon count. For instance, a cyclohexyl substituted with one or more C 1-6 -alkyl is still, within the meaning contemplated herein, a C 3-6 -cycloalkyl. Examples of a C 3-6 cycloalkylamino (alternatively referred to as -NHC 3-6 cycloalkyl) include, but are not limited to, cyclopropylamino, 2-methyl-cyclopropylamino, cyclobutylamino, 2-methyl- cyclobutylamino, cyclopentylamino, 2-methyl-cyclopentylamino, cyclohexylamino, 2-methyl-cyclohexylamino, etc. One of ordinary skill will know that said cycloalkylaminos are derived from cycloalkylamines, i.e., cycloalkyls substituted by an amine (-NH 2 ) functional group.

The term "alkoxy" refers to an -O-alkyl group or an -O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above. Examples of -O-alkyl groups include, but are not limited to, methoxy, ethoxy, «-propyloxy, z ' -propyloxy, n- butyloxy, -butyloxy, -butyloxy, etc. Examples of -O-cycloalkyl groups include, but are not limited to, -O-opropyl, -O-c-butyl, -O-c-pentyl -O-c-hexyl, etc.

The terms "alkaryl" or "alkylaryl" refer to an alkylene group having 1 to 10 carbon atoms with an aryl substituent, such as benzyl. The term "Ci -3 alkaryl" refers to a Ci -3 alkylene group with an aryl substituent. Benzyl is embraced by the term Cj. 3 alkaryl.

The term "-OCi -3 alkaryl" refers a oxygen (-0~) bound to a Ci -3 alkaryl group. Benzyloxy (-OCH 2 Ph) is embraced by the term -OCi -3 alkaryl.

The term "aryl," as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl. The aryl group can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.

The term "heteroaryl" refers to an unsubstituted or substituted aromatic heterocycle containing carbon, hydrogen, and at least one of N, O, and S. Examples of heteroaryls include, but are not limited to, a pyrrole, an imidazole, a diazole, a triazole, a tetrazole, a furan, an oxazole, an indole, a thiazole, etc. Additional examples of heteroaryls can be found in T.L. Gilchrist, in "Heterocyclic Chemistry," John Wiley & Sons, 1985. The heteroaryl group can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.

The term "heterocycle" or "heterocyclyl" refers to an unsubstituted or substituted radical containing carbon, hydrogen and at least one of N, O, and S.

Examples of heterocycles, include, but are not limited to, an aziridine, an azetidine, a pyrrolidine, a piperidine, a piperazine, etc. Additional examples of heterocycles can be found in T.L. Gilchrist, in "Heterocyclic Chemistry," John Wiley & Sons, 1985. The heterocycle can be substituted with one or more moieties selected from among alkyl, hydroxyl, F, CI, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999. The terms "alk(heteroaryl)" and "alk(heterocyclyl)" refers to a Ci -6 -alkylene group with a heteroaryl and heterocyclyl substituent, respectively.

The term "cycloheteroalkyl" refers to an unsubstituted or substituted heterocycle, in which the heterocycle contains 2 to 9 carbon atoms; preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms. Examples of cycloheteroalkyls include, but are not limited to, aziridin-l-yl, aziridin-2-yl, iV-Ci, 3 -alkyl-aziridin-2-yl, azetidinyl, azetidin-l-yl, N-Ci_ 3 -alkyl-azetidin-m'-yl, pyrrolidin-m'-yl, pyrrolidin-1- yl, 7V-Ci -3 -alkyl-pyrrolidin-m'-yl, piperidin-m'-yl, piperidin-l -yl, and N-Ci -3 -alkyl- piperidin-m'-yl, where m' is 2, 3, or 4 depending on the cycloheteroalkyl. Specific examples of N-Ci -3 -alkyl-cycloheteroalkyls include, but are not limited to, N- methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl- pyrrolidin-4-yl, N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, and N-methyl- piperidin-4-yl. In the instance of R 10 , R 16 , and R 17 , the point of attachment between the cycloheteroalkyl ring carbon and the ring occurs at any one of m'.

The term "acyl" refers to a substituent containing a carbonyl moiety and a non-carbonyl moiety and is meant to include an amino-acyl. The carbonyl moiety contains a double-bond between the carbonyl carbon and a heteroatom, where the heteroatom is selected from among O, N and S. When the heteroatom is N, the N is substituted by a

Ci- 6 - The non-carbonyl moiety is selected from straight, branched, and cyclic alkyl, which includes, but is not limited to, a straight, branched, or cyclic Ci-20 alkyl, CMO alkyl, or a Ci -6 -alkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyl optionally substituted with halogen (F, CI, Br, I), hydroxyl, Q to C 4 alkyl, or Ci to C 4 alkoxy, sulfonate esters, such as alkyl or aralkyl sulphonyl, including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least one aryl group is present in the non-carbonyl moiety, it is preferred that the aryl group comprises a phenyl group.

The term "C 2-7 acyl" refers to an acyl group in which the non-carbonyl moiety comprises a Ci -6 alkyl. Examples of a C 2-7 -acyl, include, but are not limited to: -C(0)CH 3 , -C(0)CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , -C(0)CH(CH 3 )CH 2 CH 3 , - C(0)C(CH 3 ) 3 , etc. The term "aminoacyl" includes Ν,Ν-unsubstituted, N,N-monosubstituted, and Ν,Ν-disubstituted derivatives of naturally occurring and synthetic α, β γ or δ amino acyls, where the amino acyls are derived from amino acids. The amino- nitrogen can be substituted or unsubstituted or exist as a salt thereof. When the amino-nitrogen is substituted, the nitrogen is either mono- or di-substituted, where the substituent bound to the amino-nitrogen is a Ci_ 6 alkyl or an alkaryl. In the instance of its use for the compound of formula I, it is understood that an

appropriate atom (O or N) is bound to the carbonyl carbon of the aminoacyl.

CH 2 CH(CH 3 )CH 2 0- C(O)alkyl), etc. As the expression "acyl" encompasses "aminoacyl," further contemplated radicals include but are not limited to C 1-6 -alkyl- oxy-aminoacyl, where aminoacyl is defined above. The term "alkenyl" refers to an unsubstituted or a substituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or more olefinic double bonds. The term "C 2- N alkenyl" refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. For example, the term "C2- 10 alkenyl" refers to an alkenyl comprising 2 to 10 carbon atoms. The term "C 2-4 alkenyl" refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl) or 2- butenyl (crotyl). It is understood that the alkenyl or C 2- N-alkenyl can be substituted with one or more radicals selected from among alkyl, halo, alkoxy, aryloxy, nitro, and cyano.

The term "vinyl," which is embraced by the term "C 2-4 alkenyl," refers to -CR— CR"R"', where R', R", and R'" are independently selected from among hydrogen, Ci -6 -alkyl, halo, and Ci -6 -alkoxy. Examples of a vinyl include, but are not limited to, ethenyl (-CH=CH 2 ), 2-bromo-ethenyl (-CH=CHBr), etc.

The term "ethynyl," as used herein, refers to -C≡CR', where R' is selected from among hydrogen, Ci -6 -alkyl, halo, and C]_ 6 -alkoxide.

The term "methine," as used herein, refers to the radical -CR— , where R' is selected from among hydrogen, Ci -6 alkyl, halo, and Ci_ 6 -alkoxide.

The term "vinylidene," as used herein, refers to >C=CRR', where R and R are independently selected from among hydrogen, Ci_ -alkyl, halo, and Ci- - alkoxide.

The Pi, P 2 , and P 3 phosphate radicals may be introduced at the 5'-OH of a nucleoside compound either by synthetic means in the lab or by enzymatic (or metabolic) means in a cell or biological fluid (either in vivo or in vitro). It is understood that the acidities of the hydroxyl (-OH) substituents vary and that salts of the phosphate radicals are possible. The term "-P*(0)(OR la )(NHCHR lb C(0)OR lc )" or "phosphoramidate" as used herein is represented by the following structure:

where R la , R lb , and R lc are as defined above. Examples of phosphoramidate moieties are described in U.S. Patent No. 7,964,580. It will be understood that the ~NHCH*(R lb )C(0)OR lc fragment can be derived from an amino acid, which is defined above.

Under the Summary, certain definitions related to R 1 , 1)1), and Y, 4)d), include the expressions "-P*(0)(OR lc )~" (see R 1 , 1)1)) and "-0~" (see Y, 4)d)). It is understood that when R 1 is "-P*(0)(OR lc )~" and Y is "-0~" or when Y is "-0~' and R 1 is "-P(0)(OR lc )~", then compound I has the structure shown on the left, where the R 1 and Y substituents are identified on the ri ht:

Y

It is understood that use of the expression "cyclophosphate" or "cyclic-phosphate" is meant to embrace the left-hand structure. These expressions likewise have the same meanings when recited as definitions for certain embodiments and aspects of those embodiments.

The term " a l ,3,2-dioxaphosphinane-2-oxide," as used herein is represented by an unsubstituted form (jl) or a substituted form (j2), as represented by the following structures:

jl) j2) where R n is selected from among hydroxy, an alkyl, a hydroxyalkyl, an aryloxide, an aryl, such as phenyl, a heteroaryl, such as pyridinyl, where the aryl and the heteroaryl can be substituted by 1 -3 substituents independently selected from among an alkyl, an alkoxy, and a halo. A preferred R n is pyridinyl which can be substituted by 1-3 substituents independently selected from among a Ci- alkyl, a Ci -6 -alkoxy, and a halo.

The term "aryloxide," or "aryloxy" as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenoxide (PhO-), p-phenyl- phenoxide (p-Ph-PhO-), or naphthoxide, preferably the term aryloxide refers to substituted or unsubstituted phenoxide. The aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, -C(0)(Ci -6 alkyl), -C(0)0(Ci -6 alkyl), amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.

The term "4H-benzo[d][l,3,2]dioxaphosphine-2-oxide," as used herein is represented by an unsubstituted form (kl) or a substituted form (k2), as represented by the followin

kl) k2)

where R n and R' n , where R n is hydrogen and one alkyl radical, or two alkyl radicals independent of one another, and R' n is one, two, or three radicals selected from among alkyl, alkoxy, aryloxy, and halo. Preferably, R' n is one, two, or three radicals selected from among a Ci -6 alkyl, a C 1-6 , alkoxy, and a halo. More preferably, R' n is one radical selected from among a C 1-6 -akyl, a Ci -6 -alkoxy, and a halo.

In the event that resolution problems or printing errors might obscure the pictoral representation of B3, it is contemplated that there exists a bonding configuration represented by "^" between each one of w'^W 2 , W 2 ^C, C^W 4 , W^W 3 , and W 3 — W 1 , within the five-membered ring framework, where "^^" is understood to be a single- or double-bond. It is not contemplated that all bonding pairs contained in the five-membered ring therein are all double bonds or all single bonds. Rather, it is contemplated that when a certain definitional requirement is selected, then the bonding arrangement of the five-membered ring satisfies Huckel's rule, i.e., the total number of pi-bond and lone-pair electrons for the selected radicals is 6. For example, when W 1 is O or S, W 2 is CR 15 , W 3 is C, and W 4 is C (see 1-3-12 or 1-3-13), then the contemplated structure is:

Formula I is recited above. Implicit to formula I is the exclusion of compounds disclosed in B. R. Babu et al. Org. Biomol. Chem. (2003) 1 : 3514-3526, whether said compounds are explicitly or implicitly disclosed therein. For instance, the compounds identified there as 9b, 14b, 21, and 27, are not contemplated to be within the sco e of formula I (as well as formula 1-1 resented below

9b 14b 21 27

However, these compounds, as well as derivatives embraced by formula I, are contemplated for treating a subject infected by HCV or DENV and are contemplated for compositions useful for treating a subject infected by HCV or DENY, as explained in further detail below. The compound numbering for compounds 9b, 14b, 21, and 27 is as found in Babu et al. It should be noted that compounds 21 and 27 are exemplified herein with the numbering here of 36 and 32, respectively.

The term "effective amount" as used herein means an amount required to reduce symptoms of the disease in a subject.

The term "subject," as used herein means a mammal.

The term "medicament," as used herein means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof.

The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.

The term "excipient" as used herein refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.

As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. "Treatment" is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. The term "treatment" of an HCV infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.

The term "protecting group" which is derived from a "protecting compound," has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., -OH, -NH 2 , etc.) that allows chemical modification of at least one other functional group. Examples of protecting groups, include, but are not limited to, benzoyl, acetyl, phenyl-substituted benzoyl, tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl) group, thiopixyl (9- phenylthioxanthen-9-yl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)- alkyl, C(0)Ph, C(0)aryl,

The term "leaving group" ("LG") as used herein, has its plain and ordinary meaning for one of ordinary skill in this art. Examples of leaving groups include, but are not limited to: halogen (CI, Br, or I); tosylate, mesylate, triflate, acetate, etc.

Embodiments

A first embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula I-l

3b2) R 17 is-NH 2 or -NH(C I-6 alkyl). A twelfth aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3-5

A seventeenth aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3-8

1-3-8

wherein B' is selected from among B5, B6, B7, B8, B9, and BIO represented by the following structures

B8 B9 BIO

and R 1 , R 2 , Y, R 3 , Θ X, R 14 , R 15 , R 16 , R 17 , m, and™ have the meanings described above. An eighteenth aspect of the third embodiment is directed to a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula 1-3-8,

In the embodiments of this section, the expression "Compound I" is meant to encompass a compound or its stereoisomer or its salt or its metabolite or its deuteride thereof represented by formula I notwithstanding the excluded subject matter found in the Definitions.

A fourth embodiment is directed to a composition comprising compound I.

A first aspect of the fourth embodiment is directed to a composition for treating a subject infected with any one of hepatitis C virus, hepatitis B virus, Hepatitis A virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, bovine viral diarrhea virus, Japanese encephalitis virus, or those viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses, said composition comprising an effective amount of compound I.

A second aspect of the fourth embodiment is directed to a composition for treating a subject infected with a hepatitis C virus, which comprises an effective amount of compound I and optionally a pharmaceutically acceptable medium.

A third aspect of the fourth embodiment is directed to a composition for treating a subject infected with a dengue virus, which comprises an effective amount of compound I and optionally a pharmaceutically acceptable medium.

A fourth aspect of the fourth embodiment is directed to a composition for treating a subject infected with any one of a hepatitis B virus, a Hepatitis A virus, a West Nile virus, a yellow fever virus, a rhinovirus, polio virus, a bovine viral diarrhea virus, and a Japanese encephalitis virus, which comprises an effective amount of compound I and a pharmaceutically acceptable medium.

A fifth aspect of the fourth embodiment is directed to a composition for treating a subject infected with a hepatitis C virus, which comprises an effective amount of compound I and a pharmaceutically acceptable medium.

A sixth aspect of the fourth embodiment is directed to a composition for treating a subject infected with a dengue virus, which comprises an effective amount of compound I and a pharmaceutically acceptable medium.

A seventh aspect of the fourth embodiment is directed to a composition for treating a subject infected with a virus from any one of viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses, which comprises an effective amount of compound I and a pharmaceutically acceptable medium.

Compound I may be independently formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. Compound I is efficacious when administered by suppository administration, among other routes of administration. The most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral medication.

Compound I together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration. A typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).

As noted above, the term "effective amount" as used herein means an amount required to reduce symptoms of the disease in a subject. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.001 and about 10 g, including all values in between, such as 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.050, 0.075, 0.1 , 0.125, 0.150, 0.175, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7 0.75, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per day should be appropriate in monotherapy and/or in combination therapy. A particular daily dosage is between about 0.01 and about 1 g per day, including all incremental values of 0.01 g (i.e., 10 mg) in between, a preferred daily dosage about 0.01 and about 0.8 g per day, more preferably about 0.01 and about 0.6 g per day, and most preferably about 0.01 and about 0.25 g per day, each of which including all incremental values of 0.01 g in between. Generally, treatment is initiated with a large initial "loading dose" to rapidly reduce or eliminate the virus following by a decreasing the dose to a level sufficient to prevent resurgence of the infection. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on knowledge, experience and the disclosures of this application, to ascertain a effective amount of the compound disclosed herein for a given disease and patient.

Compound I can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard

pharmaceutical practice.

Solid form preparations include, for example, powders, tablets, pills, capsules, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Examples of solid formulations are exemplified in EP 0524579; US 2002/0142050; US 2004/0224917; US 2005/00481 16; US

2005/0058710; US 2006/0034937; US 2006/0057196; US 2006/0188570; US 2007/0026073; US 2007/0059360; US 2007/0077295; US 2007/0099902; US 2008/0014228; US 6,267,985; US 6,294,192; US 6,383,471 ; US 6,395,300; US 6,569,463; US 6,635,278; US 6,645,528; US 6,923,988; US 6,932,983; US

7,060,294; and US 7,462,608.

Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Examples of liquid formulation are exemplified in U.S. Patent Nos. 3,994,974; 5,695,784; and 6,977,257. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins,

methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Compound I may be independently formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

Compound I may be independently formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Certain of these formulations may also be used in conjunction with a condom with or without a spermicidal agent.

Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,

Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering compositions containing the compounds contemplated herein unstable or compromising their therapeutic activity.

Additionally, compound I may be independently formulated in conjunction with liposomes, micelles, or complexed to or entrapped in a protein matrix, such as albumin. As to liposomes, it is contemplated that the compound I can be formulated in a manner as disclosed in U.S. Patent Nos. 4,797,285; 5,013,556; 5,077,056;

5,077,057; 5,154,930; 5,192,549; 5,213,804; 5,225,212; 5,277,914; 5,316,771 ; 5,376,380; 5,549,910; 5,567,434; 5,736,155; 5,827,533; 5,882,679; 5,891,468; 6,060,080; 6,132,763; 6,143,321 ; 6,180,134; 6,200,598; 6,214,375; 6,224,903; 6,296,870; 6,653,455; 6,680,068; 6,726,925; 7,060,689; and 7,070,801. As to micelles, it is contemplated that compound I can be formulated in a manner as disclosed in U.S. Patent Nos. 5,145,684 and 5,091,188. As to a protein matrix, it is contemplated that compound I can be complexed to or entrapped in a protein matrix as disclosed in any one of U.S. Patent Nos. 5,439,686; 5,498,421 ; 6,096,331 ;

6,506,405; 6,537,579; 6,749,868; 6,753,006; and 7,820,788.

A fifth embodiment is directed to a use of compound I for the manufacture of a medicament for the treatment of any condition the result of an infection by any one of the following viral agents: hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus and Japanese encephalitis virus.

A first aspect of the fifth embodiment is directed to a use of compound I for the manufacture of a medicament for the treatment of a hepatitis C virus.

A second aspect of the fifth embodiment is directed to a use of compound I for the manufacture of a medicament for the treatment of a dengue virus.

A third aspect of the fifth embodiment is directed to a use of compound I for the manufacture of a medicament for the treatment of any condition the result of an infection by any one of the following viral agents: a West Nile virus, a yellow fever virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, and a Japanese encephalitis virus.

A fourth aspect of the fifth embodiment is directed to a use of compound I for the manufacture of a medicament for the treatment of any condition the result of an infection by a viral agent from any one of viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses.

As noted above, the term "medicament" means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage form, and the like, comprising compound I. It is contemplated that the use of any of compound I for the manufacture of a medicament for the treatment of any of the antiviral conditions disclosed herein, either alone or in combination with another compound disclosed herein. A medicament includes, but is not limited to, any one of the compositions contemplated by the fourth embodiment disclosed herein.

A sixth embodiment is directed to a method of treating a subject infected with any one of a hepatitis C virus, a West Nile virus, a yellow fever virus, a degue virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, a Japanese encephalitis virus or those viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses, said method comprising administering an effective amount of compound I to the subject.

A first aspect of the sixth embodiment is directed to a method of treating a subject infected with a hepatitis C virus, said method comprising administering an effective amount of compound I to the subject.

A second aspect of the sixth embodiment is directed to a method of treating a subject infected with a dengue virus, said method comprising administering an effective amount of compound I to the subject. A third aspect of the sixth embodiment is directed to a method of treating a subject injected with any one of a West Nile virus, a yellow fever virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, a Japanese encephalitis virus or those viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses, said method comprising administering an effective amount of compound I to the subject.

It is intended that a subject in need thereof is one that has any condition the result of an infection by any of the viral agents disclosed herein, which includes, but is not limited to, a hepatitis C virus, a West Nile virus, a yellow fever virus, a dengue virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus or a Japanese encephalitis virus; flaviviridae viruses or pestiviruses or hepaciviruses or a viral agent causing symptoms equivalent or comparable to any of the above-listed viruses.

As noted above, the term "subject" means a mammal, which includes, but is not limited to, cattle, pigs, sheep, buffalo, llama, dogs, cats, mice, rats, monkeys, and humans, preferably the subject is a human. It is contemplated that in the method of treating a subject thereof of the ninth embodiment can be any of the compounds contemplated herein, either alone or in combination with another compound disclosed herein.

Therapeutic efficacy can be ascertained from tests of liver function including, but not limited to protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism. Alternatively the therapeutic effectiveness may be monitored by measuring HCV-RNA. The results of these tests will allow the dose to be optimized.

A fourth aspect of the sixth embodiment is directed to a method of treating a subject infected with hepatitis C virus or a subject infected with a dengue virus, said method comprising administering to the subject an effective amount of compound I and an effective amount of another antiviral agent; wherein the administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any sub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, and 23 hours. It will be understood that the effective amount of compound I and the effective amount of another antiviral agent can be formulated in the same dosage form or formulated in separate dosage forms.

A fifth aspect of the sixth embodiment comprises adding to the 3'-terminus of an HCV RNA strand or a DENV RNA strand a radical or its salt thereof represented by

where is the point of attachment to the 3 '-terminus. It is understood that addition of said compound to the nascent RNA strand will prevent or substantially increase the likelihood that propagation of the RNA strand having said compound added thereto will come to an end.

A seventh aspect of the sixth embodiment comprises increasing an intracellular concentration of a triphosphate (P 3 ) compound or its salt thereof represented by

in a cell infected with HCV or DENV.

When compound I is administered in combination with another antiviral agent the activity may be increased over the activity exhibited for compound I alone. When the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives. "Concurrent administration" as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.

It will be understood that references herein to treatment extend to

prophylaxis as well as to the treatment of existing conditions.

Examples of "another antiviral agent" include, but are not limited to: HCV

NS3 protease inhibitors (see EP 1881001 , US 2003/0187018, US 2005/0267018, US 2003/0119752, US 2003/0187018, US 2005/0090432, US 2009/0291902, US 2005/0267018, US 2005/0267018, US 201 1/0237621, US 2009/0281 141, US 2009/0105302, US 2009/0062311 , US 2009/0281140, US 2007/0054842, US 2008/0108617, and US 2008/0108617); HCV NS5B Inhibitors (see US

2004/0229840, US 2005/0154056, US 2005/0098125, US 2006/0194749, US 2006/0241064, US 2006/0293306, US 2006/0040890, US 2006/0040927, US 2006/0166964, US 2007/0275947, US 6,784,166, US 2007/0275930, US

2002/0147160, US 2002/0147160, US 2003/0176433, US 2004/0024190, US 2005/0043390, US 2005/0026160, US 2004/0171570, US 2005/0130923, US 2008/0146788, US 2007/0123484, US 2007/0024277, US 2007/0004669, US 2004/0142989, US 2004/0142993, US 2006/0004063, US 2006/0234962, US 2007/0231318, US 2007/0142380, WO 2004/096210, US 2007/0135363, WO 2005/103045, US 2008/0021047, US 2007/0265222, US 2006/0046983, US 2008/0280842, WO 2006065590, US 2006/0287300, WO 2007039142, WO 2007039145, US 2007/0232645, US 2007/0232627, WO 2007088148, WO

2007092000, and US 2010/0234316); HCV NS4 Inhibitors (see US 2005/0228013 and US 2007/0265262); HCV NS5A Inhibitors (see US 2006/0276511, US

2007/0155716, US 2008/0182863, US 2009/0156595, and US 2008/0182863); Toll- like receptor agonists (see US 2007/0197478); and other inhibitors (see US

2003/0207922, US 2006/0094706, US 2006/0122154, US 2005/0069522, US 2005/0096364, US 2005/0069522, US 2005/0096364, and US 2005/0215614); PSI- 6130 (US 7,429,572); RG7128 (US 7,754,699); Compound A (disclosed in US 2010/0081628, see also compound 19a (PSI-938) and 19b disclosed in the same application, which are individual diastereomers of compound A); PSI-7977 (US 7,964,580, claim 8) and PSI-7976 (disclosed in US 2010/0016251 and US

2010/0298257 (12/783,680) (PSI-7977 (Sp-4) and PSI-7976 (Rp-4)); PSI-353661 (disclosed in US 2010/0279973, see compound 11); telaprevir (also known as VX- 950, which is disclosed in US 2010/0015090); boceprevir (disclosed in US 2006/0276405); BMS-790052 (disclosed in US 2008/0050336, see also US

The antiviral agents can be formulated in a manner known to one of ordinary skill. The respective patent documents provide guidance for the respective formulations. The preferred dosage forms of the antiviral agents are those that are approved by the FDA. However, not to be limited, contemplated dosage forms of the antiviral agents are contemplated as follows: RG7128 (500 mg, 1000 mg, or 1500 mg); Compound A (5 mg to 1000 mg and values inbetween); PSI-7977 (100 mg, 200 mg, or 400 mg); A dosage form for VX-950 is disclosed in McHutchison et al. N. Engl. J. Med. (2009) 360(18): 1827-1838; see also WO 2009/038663;

Boceprevir (WO 2009/038663).

Additional examples of "another antiviral agent" and contemplated dosages are identified in the following table.

ANA598 Polymerase Anadys Phase II First day

According to the FDA-approved label dated October 8, 2010, the

recommended dose of COPEGUS (ribavirin) tablets depends on body weight and the HCV genotype to be treated, as shown in the following table.

The COPEGUS label further discloses that the recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks. The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen.

An eighth embodiment is directed to a compound or a salt thereof represented by formula A,

A

1 2 3

wherein each one of Z , Z , and Z is hydrogen or a protecting group (PG).

In a first aspect of the eighth embodiment, PG is selected from among - C(0)alkyl, -C(0)aryl, -C(0)0(Ci_ 6 alkyl), -C(0)0(C 1-6 alkylene)aryl, -C(0)Oaryl, - CH 2 0-alkyl, -CH 2 0-aryl, -S0 2 -alkyl,-S0 2 -aryl, and a silicon-containing protecting group. One of ordinary skill will appreciate that Z 1 and Z 2 can be the same, while Z 3 is different or that Z 1 and Z 2 are a part of the same radical, such as in the instance of ~Si(C]. 6 alkyl) 2 OSi(Ci -6 alkyl) 2 ~, which would be derived from, for example, a 1,3- dihalo- 1 , 1 ,3 ,3 -tetra(C \ -6 alkyl)disiloxane.

In a third aspect of the ninth embodiment, the nucleophile is comprised of a Ci -6 alkylthiolate. The C 1-6 alkyl thiolate is obtained from methylthiol, ethylthiol, propylthiol, /-propyl thiol, n-butylthiol, z-butylfhiol, s-butylthiol, i-butylthiol, n- pentylthiol, isopentylthiol, neopentylthiol, t-pentylthiol, and hexylthiol.

In a fourth aspect of the ninth embodiment, the nucleophile is comprised of a

-NH(C 1-6 alkyl). The -NH(Cj -6 alkyl) is obtained from methylamine, ethylamine, propylamine, /-propylamine, n-butylamine, /-butylamine, s-butyl amine, t- butylamine, n-pentylamine, isopentylamine, neopentylamine, t-pentylamine, and hexylamine. In a fifth aspect of the ninth embodiment, the nucleophile is comprised of a - cycloalkylamino. The cycloalkylamino is derived from its respective

cycloalkylamine.

In a sixth aspect of the ninth embodiment, the nucleophile is comprised of a -C 3-6 cycloalkylamino. The -C 3-6 cycloalkylamino is obtained from

tetraalkyammonium, such as tetra-n-butyl-ammonium ( ,! Bu 4 N + ). However, M can be other cationic species so long as the association with the nucleophile permits reaction with A.

In each of the first six aspects of the ninth embodiment, the nucleophile can be pre-formed or prepared in situ. A pre- formed nucleophile can be obtained commercially or prepared by procedures known to one of ordinary skill. The so- prepared pre-formed nucleophile can optionally be isolated as a solid or used directly in the reaction of the ninth embodiment. A nucleophile prepared in situ may occur in the presence or absence of compound A. In the instance of a pre-formed nucleophile or a nucleophile prepared in situ, the solvent used depends on the conditions of the reaction. In certain aspects a suitable solvent is a polar aprotic solvent. Examples of polar aprotic solvents include, but are not limited to, DMSO, HMPA, DMF, THF, 2-methyl-THF, dioxane, cyclopentylmethylether, t-butyl- methylether, etc. In other aspects the nucleophile is obtained directly from the solvent. For example, the solvent for the solvent for the first aspect of the ninth embodiment could be an C^alcohol (e.g., methanol, ethanol, etc.), in which the C^ 6 alkoxide can be obtained according to conventional procedures. Solvents for the second and third aspects of the ninth embodiment include polar aprotic solvent, as well as an alcoholic solvent. The solvent for the fourth aspect of the ninth embodiment could be a Ci -6 alkylamine (e.g., methylamine, ethylamine, etc.), in which the

Ci -6 alkylamide is obtained by adding a base having sufficient basicity to obtain the desired nucleophile. Likewise, the solvent for the fifth and sixth aspects of the ninth embodiment could be a cycloalkyl amine or a C 3-6 cycloalkylamine (e.g.,

cyclopropyl amine, cyclobutylamine, etc.), in which the cycloalkylamide or the

C3 -6 cycloalkylamide is obtained by adding a base having sufficient basicity to obtain the desired nucleophile. The optional deprotection step is done by conventional means.

A seventh aspect of the ninth embodiment is directed to a process for preparing a compound represented by formula 1-3-5', which comprises reacting compound A' with a nucleophile to obtain compound B', wherein the nucleophile is comprised of a radical selected from among a -0(Ci -6 alkyl), a -OCi_ 3 alkaryl, a - NH(Ci -6 alkyl), and a C 3- cycloalkylamino, and wherein for compound 1-3-5', R la and R lc are as defined, and R 16 is a -0(C,_ 6 alkyl). a -OCi -3 alkaryl, a -NH(C 1-6 alkyl), and a C 3 _ 6 cycloalkylamino .

An eighth aspect of the ninth embodiment is directed to a process for preparing a compound represented by formula 1-3-5', which comprises reacting compound A' with a nucleophile to obtain compound B', wherein the nucleophile is comprised of a radical selected from among a -0(Ci_ 6 alkyl) and a -OCj_ 3 alkaryl, and wherein for compound 1-3-5', R la are R lc are as defined, and R 16 is a -0(Ci- 6 alkyl) or a -OCi^alkaryl.

A ninth aspect of the ninth embodiment is directed to a process for preparing a compound represented by formula 1-3-5', which comprises reacting compound A' with a nucleophile to obtain compound B', wherein the nucleophile is comprised of a -0(Ci -6 alkyl), and wherein for compound 1-3-5', R la and R lc are as defined, and R 16 is a -0(C 1-6 alkyl).

A tenth aspect of the ninth embodiment is directed to a process for preparing a compound represented by formula 1-3-5', which comprises reacting compound A' with a nucleophile to obtain compound B', wherein the nucleophile is comprised of a

-OC 1-3 alkaryl, and wherein for compound 1-3-5', R la and R lc are as defined, and R 16 is a

-OC 1-3 alkaryl. In an eleventh aspect of the ninth embodiment, PG is selected from among - C(0)alkyl, -C(0)aryl, -C(0)0(C 1-6 alkyl), -C(0)0(C 1-6 alkylene)aryl, -C(0)Oaryl, - CH 2 0-alkyl, -CH 2 0-aryl, -S0 2 -alkyl,-S0 2 -aryl, and a silicon-containing protecting group. One of ordinary skill will appreciate that Z 1 and Z 2 can be the same, while Z 3 is different or that Z 1 and Z 2 are a part of the same radical, such as in the instance of ~Si(Ci -6 alkyl) 2 OSi(Ci_ 6 alkyl) 2 ~, which would be derived from, for example, a 1 ,3- dihalo- 1 , 1 ,3 ,3 -tetra(C j -6 alkyl)disiloxane.

In a second aspect of the tenth embodiment, R 16 is -0(C 1-6 alkyl). In a third aspect of the tenth embodiment, R 16 is -OCi_ 3 alkaryl.

In a fourth aspect of the tenth embodiment, R 16 is -S(Ci -6 alkyl).

In a fifth aspect of the tenth embodiment, R 16 is -NH(C 1-6 alkyl).

In a sixth aspect of the tenth embodiment, R 16 is -NHC 3-6 cycloalkyl.

In a seventh aspect of the tenth embodiment, the mole ratio of the £p- diastereomer to the i? P -diastereomer ranges from about 2 to about 99.99 and all values in between, including 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,

75, 80, 85, 90, 95, 97, 98, 99, 99.9, and 99.99.

In an eighth aspect of the tenth embodiment, the mole ratio of the R P - diastereomer to the Sp-diastereomer ranges from about 2 to about 99.99 and all values in between, including 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,

75, 80, 85, 90, 95, 97, 98, 99, 99.9, and 99.99.

In a ninth aspect of the tenth embodiment, the meanings of the protecting group for A" is as described for A in the eighth embodiment.

An eleventh embodiment is directed to a process for preparing a compound represented by formula 1-3-5"'

The disclosed reagents are meant to be exemplary only and should not be meant to narrow the scope of the embodiments disclosed below.

A seventh embodiment is directed to a process for preparing a compound or its stereoisomer or its salt or its metabolite or its deuteride represented by formula I, by any of the processes disclosed herein.

A first aspect of the seventh embodiment is directed to a process for preparing a compound or its stereoisom its salt or its metabolite or its deuteride thereof wherein I z J is , said process comprising any one of the following reaction steps a'-h'

PG

103 Scheme 2. General Synthesis of 2'-Spiro-ribo-nucleosides

19 18 17 21

Reagents and conditions: a) Silylated base/TMSOT or Sn Cl 4 or

base/TMSOTf/DBU; b) NH 3 /MeOH; c) TIPSCl/Pyr.; d) BH 3 /H 9 0 2 ; e)

MsCl/Pyr; f) NaH; g) NH 4 F; h) 1. Os0 4 /NMO, 2. NaI0 4 , 3. NaBH 4

A second aspect of the seventh embodiment is directed to a process for preparing a compound or its stereoisomer or its salt or its metabolite thereof represented by formula I, wherein °-- , said process

comprising any one of the following reaction steps a'-h'

wherein B is as defined above, PG and PG' are independent of one another leaving groups, and LG is a leaving group. Scheme 3-6 provide general procedures for preparing additional compounds of formula I. In these schemes, Pg, represents a protecting group, which is defined herein. R is a substituent that provides for or is defined by the substituent " Y" as defined herein. As described above, examples of protecting groups are defined herein and disclosed in Protective Groups in Organic Synthesis, 3 nd ed. T. W.

Greene and P. G. M. Wuts, John Wiley & Sons, New York, N. Y., 1999. One of ordinary skill will appreciate the conditions available to protect and deprotect a given synthetic intermediate. Additionally, it is contemplated that one of ordinary skill would employ known procedures for the deoxygenation steps disclosed below. Scheme 3. General Procedure for preparing 2'-spiro-(l ,3-dioxolan-5-yl)

Procedures for preparing nucleosides and nucleotides containing the "B" of Compound 1-3-1 are disclosed in any one of WO 2010/075517, WO 2010/075549, and WO 2010/075554.

Procedures for preparing nucleosides and nucleotides containing the "B6" of Compound 1-3-7 (or 1-3-9) are disclosed in any one of WO 2010/002877 and WO 2009/132135.

Procedures for preparing nucleosides and nucleotides containing the "B7" of

Compound 1-3-7 (or 1-3-10) are disclosed in any one of WO 2010/036407, WO 2009/132135, and WO 2009/132123.

Procedures for preparing nucleosides and nucleotides containing the "B8" of Compound 1-3-7 (or 1-3-11) are disclosed in WO 2009/132123.

Procedures for preparing nucleosides and nucleotides containing the "B9" of

Compound 1-3-7 (or 1-3-12) are disclosed in WO 2010/036407.

Procedures for preparing nucleosides and nucleotides containing the "B10" of Compound 1-3-7 (or 1-3-13) are disclosed in WO 2010/093608.

Procedures for preparing deuterides are known to one of ordinary skill and reference can be made to US 2010/0279973 and procedures disclosed therein.

Procedures for preparing compound 1-3-5"' are disclosed herein. Additional procedures for preparing and isolating compound C are disclosed in US 13/076,552 (US 2011/0251152), filed on March 31 , 2011 and US 13/076,842 (US

2011/0245484), filed on March 31, 201 1. To the extent necessary, the subject matter of US 13/076,552 and US 13/076,842 is hereby incorporated by reference.

Examples

Not to be limited by way of example, the following examples serve to facilitate a better understanding of the disclosure.

In the examples that follow, certain abbreviations have been used. The following table provides a selected number of abbreviations. It is believed that one of ordinary skill would know or be able to readily deduce the meaning of any abbreviations not specifically identified here. Abbreviation Meaning

The following scheme describes a possible synthetic route for the preparation of 2'-spiro-ara-uracil analogs, 32 and 36. A synthetic intermediate common to compounds 32 and 36 is compound 28, which is obtained by protecting uridine 25 with l,3-dichloro-l,l ,3,3-tetraisopropyldisiloxane (TIPSCl) followed by oxidation of the 2'-carbon to form compound 27. Compound 28 is prepared by reacting compound 27 with an appropriate allyl-containing reagent.

To a solution of compound 31 (150 mg, 0.285 mmol) in anhydrous THF (10 mL) was added Et 3 N*3HF (0.3 mL) and the mixture was stirred at room temperature for 2 h. The mixture was then evaporated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (0-15% MeOH in

28 33 To a solution of compound 28 (4.8 g, 9.12 mmol) in DCM (200 niL) was bubbled with 0 3 and the solution was stirred at -78°C for 3h. To the solution were added Me 2 S (1 mL) and NaBH 4 (1.73 g, 45.60 mmol) at room temperature and the mixture was stirred overnight. The resulting solution was washed with H 2 0 and the solvent was evaporated. The residue was purified by silica gel column

To a solution of compound 35 (300 mg, 0.585 mmol) in anhydrous THF (10 ml) was added Et 3 N » 3HF (0.15 mL) and the mixture was stirred at room temperature for 2 h. The mixture was then evaporated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (0-15% MeOH in

To a solution of 39 (0.60 g, 2.1 1 mmol) in pyridine (10 mL) and CH 2 C1 2 (20 mL) was added TIPSC1 at 0°C within 10 min. The solution was stirred at room temperature for 24h. Solvent was evaporated and the residue was dissolved in EtOAc (100 mL). The solution was washed with brine and dried over Na 2 S0 4 . Solvent was evaporated and the residue was purified by silica gel column chromatography (0-5% MeOH in CH 2 C1 2 ) to give product 40 (1.00 g, 90%) as a syrup.

temperature for lh. To the solution was added NH 4 OH (30%, 2 mL) and the mixture was stirred at room temperature for lh. Solvent was evaporated to dryness and the residue was co-evaporated with toluene twice to give crude cytosine analog which was dissolved in CH 2 C1 2 (10 mL) and pyridine (1 mL). To the solution was added BzCl (0.1 mL, 0.86 mmol) and the solution was stirred at room temperature for 2h. Water (5 mL) was added and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL) and the solution was washed with water, brine and dried over Na 2 S0 4 . Solvent was evaporated and the residue was purified by silica gel column chromatography (0-60% EtOAc in hexanes) to give N-benzoylcytosine analog which was dissolved in THF (10 mL). To the solution was added TBAF (0.12 g, 0.48 mmol) and the solution was stirred at room temperature for lh. Solvent was evaporated and the residue was purified by silica gel column (0-8% MeOH in CH 2 C1 2 ) to give N-benzoyl nucleoside which was dissolved in 7N NH 3 in MeOH (8 mL) and the solution was stirred at room temperature for 20h. Solvent was evaporated and the residue was purified by silica gel column (0-30% MeOH in CH 2 C1 2 ) to give product 49 (0.09 g, 56% from 43). 1H

To a solution of compound 58 (3.0 g, 5.18 mmol) in THF (100 mL) was added solution of allylmagnesium bromide (10.36 mL, 10.36 mmol) at -78°C and the mixture was stirred for 2 h at the same temperature. Then the temperature was raised to -10°C and the reaction was quenched with H 2 0. The mixture was extracted with DCM. The organic solution was dried with Na 2 S0 4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography

To a solution of of 59 (1.20 g, 2.07 mmol) in THF (60 mL) was added BH 3 .SMe 2 (0.5 mL, excess) and the solution was stirred at 0°C for lh. To the solution was added an additional BH 3 *SMe 2 (0.5 mL, excess) and the solution was stirred at 0°C for 2h. To the resulting solution was added 2N NaOH (2 mL) followed by the addition of H 2 0 2 (30%, 2 mL) and the mixture was stirred at room

temperature for lh. To the mixture was added additional 2N NaOH (2 mL) followed by the addition of H 2 0 2 (30%, 2 mL) and the mixture was stirred at room

60 61 To a solution of compound 60 (0.28 g, 0.44 mmol) in CH 2 C1 2 (20 mL) and pyridine (1 mL) was added MsCl (0.3 mL, 3.88 mmol), and the solution was stirred at room temperature for 3h. Water (10 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic solution was washed with brine and dried over Na 2 S0 4 . Solvent was removed and the residue was used for the next reaction without purification.

To a mixture of compound 73 (0.30 g. 0.44 mmol) in THF (6 mL), t-Butanol (6 mL) and water (1 mL) was added 0.25% Os0 4 in t-Butanol (0.5 mL) followed by addition of 50% NMO (0.2 mL, 0.85 mmol) and the mixture was stirred at room temperature for 16 h. Solvent was evaporated and the residue was co-evaporated with toluene twice to give diol as a mixture of diastereomers which was dissolved in THF (10 mL). To the solution was added water (1 mL) followed by addition of NaI0 4 (excess) portion-wise until starting material disappeared at room temperature for 3h. EtOAc (100 mL) was added and the solution was washed with brine and dried over Na 2 S0 4 . Solvent was evaporated and the residue was dissolved in EtOAc (10 mL) and EtOH (10 mL). To the pre-cooled solution at 0°C was added NaBH 4 (50.16 mg, 1.32 mmol) and the mixture was stirred at 0°C for lh. EtOAc (100 mL) was added and the residue was purified by silica gel column chromatography (0- 10% MeOH in CH 2 C1 2 ) to give compound 74 (0.14 g, 43% from 73). 'NMR (400 MHz CDCI3): 5: 8.57 (s, 1H), 8.48 (s, 1H), 7.70 (m, 5H), 6.26 (s, 1H), 4.15 (m, 9H), 1.28 (m, 2H), 1.15 (m, 28H). LC-MS (ESI): 688 [M+H] + .

Step 2. Preparation of compound 75.

74 75

To a solution of compound 74 (0.33 g, 0.47 mmol) in CH 2 C1 (30 mL) and pyridine (3 mL) was added MsCl (0.1 1 g, 0.94 mmol) and the solution was stirred at room temperature for 3 h. Water (10 mL) was added and the mixture was extracted with EtOAc (100 mL). The solution was washed with brine and dried over Na 2 S0 4 . Solvent was evaporated and the residue was purified by silica gel column

Compound 87 is prepared using an eight-step reaction sequence that begins with adenine (78). Step 1: Preparation of compound 79

78 79

Compound 78 (30.0 g, 112.26 mmol) was dried by co-evaporation with anhydrous pyridine three times and dissolved in dry pyridine (400 mL). To the solution was added TMSCl (60.98 g, 561.3 mmol) and the solution was stirred for lh at 0°C. To the resulting solution was added benzoyl chloride (78.9 g, 561.3 mmol) dropwise and the mixture was stirred 3h at room temperature. The mixture was cooled to 0°C and H 2 0 (120 mL) was added, and the resulting mixture was stirred for 0.5 h. NH 3 .H 2 0 (30%, 230 mL) was added and the mixture was stirred for 2h. Solid was collected by filtration and washed with H 2 0 and EtOAc to give crude product 79. (38.0 g, 91.6 %)

To a solution of compound 79 (38.0 g, 102.33 mmol) in anhydrous pyridine (200 mL) was added TIPSC1 (38.7 g, 122.8 mmol) and the mixture was stirred for 20h at room temperature. Solvent was removed under reduce pressure and the residue was dissolved in EtOAc (200 mL). The solution was washed with H 2 0 and the solvent was removed to give 80 which was used for next step without further purification. (45.0 g, 71.62 %)

To a solution of compound 81 (4.0 g, 6.9 mmol) in THF (100 mL) was added a solution of allylmagnesium bromide (13.82 mL, 3.82 mmol) at -78°C and the resulting mixture was stirred for 2 hours at the same temperature. Then the temperature was increased to -10°C and the reaction mixture was quenched with

To a solution of compound 82 (1.6 g, 2.45 mmol) in DCM (100 mL) was bubbled with O 3 at -78°C and the slution was stirred at the same temperature for 3h. To the solution was added 1 ml of Me 2 S followed by addition of NaB¾ (92.5 mg, 2.45 mmol) at room temperature. The mixture was stirred overnight. The solution was washed with H 2 0 and the solvent was removed to give a crude product which was purified by silica gel column chromatography (hexane:EtOAc = 1 : 1) to give compound 83 (1.0 g, 62.1 %).

Step 6: Preparation of compound 84

83 84

A solution of MsCl (0.349 g, 3.04 mmol) in anhydrous CH 2 C1 2 (3 mL) was added dropwise to a solution of nucleoside 83 (1.0 g, 1522 mmol) in anhydrous pyridine (5.0 mL) at room temperature. After stirring for 12 h, methanol (5.0 mL) was added and the resulting mixture was evaporated to dryness under reduced pressure. The residue was co-evaporated with anhydrous toluene (2 x 5 mL) then dissolved in CH 2 Cl2 (50 mL). The solution was washed with saturated aqueous NaHC0 3 (2 x 25 mL). The combined aqueous phase was extracted with CH 2 C1 2 (50 mL). The combined organic phase was dried (Na 2 S0 4 ) and solvent was evaporated to dryness under reduced pressure to give compound 84 which was used for the next reaction without further purification.

Step 7: Preparation of compound 85

84 85

To a stirred suspension of NaH (180 mg, 4.50 mmol) in anhydrous THF (10 mL) was added a solution of compound 84 (1.0 g, 1.50 mmol) in THF (5 mL) at 0°C. After stirring at room temperature for 2 h, ice- water (10 mL) was slowly added. CH 2 C1 2 (50 mL) was added and the separated organic phase was washed with saturated aqueous NaHC0 3 (2 x 20 mL). The combined aqueous phase was extracted with CH 2 C1 2 (25 mL). The combined organic phase was dried (Na 2 S0 4 ) and the solvent was evaporated to dryness under reduced pressure to provide 85 which was used for the next reaction without further purification. Step 8: Preparation of compound 86

85 86

To a stirred solution of compound 85 (1.0 g, 1.55 mmol) in anhydrous methanol (50 mL) was added NaOMe (0.5 g, 9.26 mmol) and the solution was stirred at room temperature for 20 h. The solution was filtered and the filtrate was evaporated to give crude product 86.

Step 9: Preparation of compound 87.

86

87

To a stirred solution of compound 86 (0.8 g, 1.49 mmol) in anhydrous methanol (30 mL) was added NH 4 F (550 mg, 14.9 mmol) and the mixture was heated at reflux for 10 h. The mixture was filtered and the filtrate was evaporated to give a crude product which was purified by silica gel column chromatography

In the preparation of 94, it is possible to forego protection of the 6-amino- purine, which means that 94 can be prepared from adenine (78) using a seven-step sequence. Step 1: Preparation of compound 88

78 88

To a solution of compound 78 (30.0 g, 112.0 mmol) in anhydrous pyridine (200 mL) was added TIPSC1 (342.5 g, 113.5 mmol) at 0°C. The mixture was stirred overnight and the solvent was removed under reduce pressure. The residue was dissolved in EtOAc (200 mL). The solution was washed with H 2 0 and the solvent was removed to give 88 which was used for next reaction without further purification.

Step 2: Preparation of compound 89

88 89

To a solution of Cr0 3 (21.2 g, 212 mmol), anhydrous pyridine (32.42 mL, 414 mmol) and Ac 2 0 (20.3 ml, 212 mmol) was added compound 88 (54.0 g, 106 mmol) at 0°C. The mixture was stirred for 1 h and passed through a short silica gel column. The solvent was removed and the residue was co-evaporation with anhydrous toluene twice to give a crude compound 89 which was used for the next reaction without further purification. Step 3: Preparation of compound 90

89 90

To a solution of compound 89 (31.0 g, 61.1 mmol) in THF (300 mL) was added a solution of allylmagnesium bromide (122 mL, 122 mmol) in THF (50 mL) at - 78°C and the solution was stirred for 2h at the same temperature. The temperature was then raised to -10°C and the reaction mixture was quenched by addition of NH 4 CI solution and the mixture was extracted with DCM. The organic layer was dried over Na 2 S0 4 and the solvent was removed under reduced pressure. The residue was puriflcated by silica gel column chromatography (hexane:EtOAc = 3: 1) to give product 90 (8.0 g, 23.8%).

101 102 To a solution of compound 101 (0.09 g, 0.16 mmol) in CH 2 C1 2 (10 mL) and pyridine (1 mL) was added TMSC1 (0.1 mL) and the solution was stirred at 0°C for lh. To the solution was added BzCl (0.1 mL) and the resulting solution was stirred at 0°C for lh and room temperature for 4h. 30% NH 4 OH (3 mL) was added and the solution was stirred at room temperature for lh. EtOAc (100 mL) was added and the solution was washed with brine and dried over Na 2 S0 4 . Solvent was removed and the residue was dissolved in MeOH (10 mL). To the solution was added 30% NH 4 OH (1 mL) and the solution was stirred at room temperature for lh. Solvent was removed and the residue was purified by silica gel chromatography (0-10% MeOH in CH 2 C1 2 ) to give compound 102 (0.07 g, 62%) as foam. Ή NMR (400 MHz,

V. Preparation of 2'-Spiro-Ribo-(6-Substituted-Purine) Analogs 6-Substituted purine nucleosides can be prepared from common

intermediate, 6-chloropurine analogs as shown in the following scheme.

109 110 R=6-substitution

Treatment of compound 67 with methanolic ammonia gave free nucleoside 104. Selective protection of 3',5'-diol of nucleoside with TIPSC1 followed by N- benzoylation provided intermediate 106. Ozonolysis of compound 106 followed by reduction of the resulting aldehyde gave compound 107. Selective mesylation of compound 108 followed by cyclization in the presence of base, such as NaH, or NaHMDS, afforded 2'-oxetanyl compound 109. Treatment of compound 109 with TBAF provided the key intermediate for the 6-substitution. Treatment of 6- chloropurine intermediate with alcohol or amine or other nucleophile provided 6- substituted 2'-spironucleoside.

To a solution of compound 67 (6.5 g, 0.01 mol) in dry MeOH (50 mL) was added saturated NH 3 /MeOH solution (50 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was

Compound 104 (0.5 g, 1.4 mmol) in anhydrous pyridine (10 mL) at 0°C was stirred for 30 min untill the solid was dissolved completely. To the solution was added TIPSCl (0.7 g, 2.2 mmol) dropwise and the stirring was continued at 0°C for 3h. Water (2 mL) was added and the solvent was removed under reduced pressure. The mixture was dissolved in EtOAc and the solution was washed with water, brine, and dried over MgS0 4 . Solvent was evaporated to give crude compound 105 (0.75 g, yield: 88 %). LC-MS (ESI): 584 [M+H] + .

To a solution of compound 108 (2.8 g, 3.6 mmol) in THF (20 mL) was added 2M NaHMDS (5 mL, 10 mmol ) in one portion at -20°C. The reaction mixture was stirred for 2h, during which the temperature rose to 0°C gradually. The reaction mixture was diluted with EtOAc (200 mL) and washed with a solution of ammonium chloride three times. The solution was concentrated in vacuo to give crude compound 109 which was used for the next reaction without further purification. LC-MS (ESI): 692 [M+H] + . Step 7: Preparation of 110

In addition of phosphoramidate analogs, cyclic phosphates are also contemplated. To that end, procedures for preparing cyclic phosphates are disclosed in U.S. Patent Application No. 12/479,075 (US 2010/0081628), filed on June 5, 2009.

Procedures for preparing certain phosphorus-containing compounds are disclosed in U.S. Patent No. 4,816,570.

Procedures for preparing a l,3,2-dioxaphosphinane-2-oxide are disclosed in U.S. Patent No. 6,752,981 and US 2009/0209481.

Procedures for preparing a 4H-benzo[d] [ 1 ,3 ,2]dioxaphosphin-2-oxide are disclosed in U.S. Patent No. 6,312,662.

Procedures for preparing certain 3',5'-diacyl derivatives are disclosed in U.S. Patent No. 7,754,699, see also U.S. Patent No. 5,246,937 for examples of diacyl derivatives.

Procedures for preparing aminoacyl derivatives are disclosed in U.S. Patent

The unprotected nucleoside (0.10 mmol) was dissolved in DTP and cooled to 0-5 °C while maintaining an inert atmosphere. To the stirred solution was added freshly distilled phosphorus oxychloride (0.30 mmol). After lh at 0-5 °C, tributylamine (0.30 mmol) and freshly dried tributyl ammonium pyrophosphate (0.25 mmol) were added. The reaction was allowed to warm to ambient temperature for 1 h and then quenched by the addition 1.0 M aqueous triethylamine bicarbonate buffer (1 mL). The reaction solution was directly applied in portions to an ion- exchange HPLC semi-preparative column (Dionex DNA-PAC) and eluted with a gradient of 0.5 M aqueous triethylammonium bicarbonate in water. The product containing fractions were combined and concentrated to dryness. The residue was then dissolved in about 5 mL water and then subjected to lyophilization to yield ca 0.01-0.02 mmol of nucleoside triphosphate as its monotriethylamine salt. XI. Biological Evaluation of Selected Analogs

To express the antiviral effectiveness of a compound, the threshold RT-PCR cycle of the test compound was subtracted from the average threshold RT-PCR cycle of the no-drug control (ACtncv)- A ACt of 3.3 equals a 1-log 10 reduction (equal to the 90% effective concentration [EC90]) in replicon RNA levels. The cytotoxicity of the test compound could also be expressed by calculating the ACt,R A values. The AACt specificity parameter could then be introduced (ACt H cv ~~

ACt r RN A ), in which the levels of HCV RNA are normalized for the rRNA levels and calibrated against the no-drug control.

Cell cytotoxicity assays. Each compound (serially diluted from 100 μΜ) was added to Huh7 (2 x 10 3 cells/well), HepG2 (2 x 10 3 cells/well), BxPC3 (2 x 10 3 cells/well), or CEM (5 x 10 cells/well) cells and allowed to incubate for 8 days at 37°C. A medium only control was used to determine the minimum absorbance value and an untreated cell. At the end of the growth period, MTS dye from the CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Promega) was added to each well and the plate was incubated for an additional 2 hours. The absorbance at 490 ran was read with a Victor3 plate reader (Perkin Elmer) using the medium only control wells as blanks. The 50% inhibition value (CC 5 0) was determined by comparing the absorbance in wells containing cells and test compound to untreated cell control wells.

The HCV NS5B reaction was performed in a 20 μΐ, mixture containing varying concentrations of the test compound, 1 μΜ of all four natural

ribonucleotides, [a- 32 P]UTP, 20 ng uL of genotype lb (-) IRES RNA template, 1 unit/uL of SUPERase » In (Ambion, Austin, TX), 40 ng uL of wild type or S282T NS5B Genotype lb, 1 mM MgCl 2 , 0.75 mM MnCl 2 , and 2 mM DTT in 50 mM Hepes buffer (pH 7.5). The reaction was quenched by adding 80 μΙ_, of stop solution (12.5 mM EDTA, 2.25 M NaCl, and 225 mM sodium citrate) after incubating at 27 °C for 30 minutes. The radioactive RNA products were separated from unreacted substrates by passing the quenched reaction mixture through a Hybond N+ membrane (GE Healthcare, Piscataway, NJ) using a dot-blot apparatus. The RNA products were retained on the membrane and the free nucleotides were washed out. The membrane was washed 4 times with a solution containing 0.6 M NaCl and 60 mM sodium citrate. After rinsing the membrane with water followed by ethanol, the membrane was exposed to a phosphorscreen and the products were visualized and quantified using a phosphorimager. The IC 5 0 values were calculated using GraFit program version 5 (Erithacus Software, Horley, Surrey, UK). All the reactions were done in duplicate and the results were reported as IC 0 ± standard error.

The biological activies of selected compounds are presented in Tables 1-5.

Dickinson, Franklin Lakes, NJ) one day prior to start of the assay and allowed to attach overnight in EMEM (ATCC Manassas, VA) +10% FBS (Invitrogen,

Carlsbad, CA) at 37°C in a humidified 5% C0 2 atmosphere. The next day, the medium was removed and the cells were infected with Dengue 2 strain New Guinea C (VR-1584, ATCC Manassas, VA) at an MOI of 0.08 pfu/cell for two hours in 50 μL EMEM+2%FBS. For both the single point and dose response assays, compounds (2 x concentration) were diluted in EMEM+2%FBS and 50 μϊ_, was added to infected cells without removing virus. Cells were incubated for 3 days at 37°C in a humidified 5% C0 2 atmosphere. The medium was aspirated and 50 μΐ, of CellTiter-Glo (Promega , Madison, WI) was added to each well and read for 0.1 seconds on a Perkin Elmer Victor3 (Waltham, MA) plate reader. Percent survival was determined by subtracting the average value of infected control wells and normalizing to the non-infected wells. The effective concentration was calculated from the dose response data by forecasting 50% cells surviving with drug treatment. Table 6. Activity of selected nucleoside phosphoramidates against dengue virus.

Priority is claimed to U.S. provisional patent application 61/417,946, filed on November 30, 2010.

Although a full and complete description is believed to be contained herein, certain patent and non-patent references may include certain essential subject matter. To the extent that these patent and non-patent references describe essential subject matter, these references are hereby incorporated by reference in their entirety. It is understood that the meanings of the incorporated subject matter are subservient to the meanings of the subject matter disclosed herein. The subject matter of US 61/417,946, filed on November 30, 2010 is hereby incorporated by reference in its entirety. The subject matter of US 13/076,552 and US 13/076,842, both filed on March 31 , 201 1 , is hereby incorporated by reference in its entirety.

The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents.